Inverted Low-copy Repeats and Genome Instability--a Genome-wide Analysis

Overview

Journal Hum Mutat

Specialty Genetics

Date 2012 Sep 12

PMID 22965494

Citations 38

Authors

Piotr Dittwald

Tomasz Gambin

Claudia Gonzaga-Jauregui

Claudia M B Carvalho

James R Lupski

Pawel Stankiewicz

Anna Gambin

Affiliations

Soon will be listed here.

Abstract

Inverse paralogous low-copy repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.

Citing Articles

Genome-wide maps of highly-similar intrachromosomal repeats that can mediate ectopic recombination in three human genome assemblies.

Fernandez-Luna L, Aguilar-Perez C, Grochowski C, Mehaffey M, Mehaffey M, Carvalho C HGG Adv. 2024; 6(2):100396.

PMID: 39722459 PMC: 11794170. DOI: 10.1016/j.xhgg.2024.100396.

A combination of long- and short-read genomics reveals frequent p-arm breakpoints within chromosome 21 complex genomic rearrangements.

Schuy J, Saether K, Lisfeld J, Ek M, Grochowski C, Lun M Genet Med Open. 2024; 2:101863.

PMID: 39669604 PMC: 11613786. DOI: 10.1016/j.gimo.2024.101863.

Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps.

Saether K, Eisfeldt J, Bengtsson J, Lun M, Grochowski C, Mahmoud M Genome Res. 2024; 34(11):1785-1797.

PMID: 39486878 PMC: 11610578. DOI: 10.1101/gr.279346.124.

DNA methylation dysregulation patterns in the 1p36 region instability.

Swierkowska-Janc J, Kabza M, Rydzanicz M, Giefing M, Ploski R, Shaffer L J Appl Genet. 2024; .

PMID: 39460848 DOI: 10.1007/s13353-024-00913-9.

Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.

Grochowski C, Bengtsson J, Du H, Gandhi M, Lun M, Mehaffey M Cell Genom. 2024; 4(7):100590.

PMID: 38908378 PMC: 11293582. DOI: 10.1016/j.xgen.2024.100590.

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